Citation or identification of any reference in this section or any section of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
Atherosclerosis is the main underlying cause of coronary heart disease and is characterized by the deposit of lipid containing plaques on endothelium of large and medium sized arteries. Atherosclerosis is thought to be initiated at dysfunctional vascular endothelium when normal laminar blood flow is disrupted. Many systemic and local factors may cause dysfunctional endothelium and lead to or trigger an inflammatory response in the vessel wall. Multiple cell types can mediate this process, including monocyte-derived macrophages. Drexler, H. 1997. Prog. Cardiovasc. Dis. 39:287. The dysfunctional endothelium allows passage of low density lipoprotein (“LDL”) cholesterol and expresses multiple adhesion molecules for platelets and inflammatory cells. The LDL cholesterol undergoes partial oxidation and causes further endothelial dysfunction while monocytes penetrate the endothelium, differentiate into macrophages, and take up oxidized LDL cholesterol. The resulting lipid-laden macrophages, also known as foam cells, accumulate in the atherosclerotic lesion and ultimately may rupture to release oxidized LDL cholesterol and cytotoxic enzymes. This triggers fibroproliferative responses from vascular smooth muscle cells and leads to the development of atherosclerotic plaques. Fuster et al. 1992. N. Engl. J. Med. 326:310; Stary, H. C. 1989. Arteriosclerosis 99:1-19.
Studies have shown Herpes viruses, such as Herpes simplex virus and Cytomegalovirus (“CMV”), can increase the risk of developing heart disease. Roivainen et al. 2000, Circulation 101(3):252. For example, elevated CMV antibody titres are associated with the presence of atherosclerosis. Melnick et al. 1990. JAMA 263:2204; Danesh et al. 1997, Lancet 350:430; Cheng et al. 2000, Expert Opin. Investig. Drugs 9(11):2505. Based on pathological data demonstrating CMV DNA sequences and viral inclusions in atherosclerotic lesions, 75 consecutive patients undergoing directional coronary atherectomy for coronary disease were studied to see if a link between CMV infection and arterial disease exists. The results showed that patients who were seropositive for CMV prior to the procedure have a greater than five-fold increased rate arterial disease. Zhou et al. 1996. N. Engl. J. Med. 335:624.
A mechanism by which CMV may affect atherosclerosis hinges on the mononuclear phagocyte. CMV integrates into mononuclear cell precursor DNA thereby causing circulating monocytes to be a vector for delivering virus to sites of vessel inflammation. Guetta et al. 1997. Circ. Res. 81:8. Macrophages have been shown to be a similar source of circulating HUV in patients with AIDS. Orenstein et al. 1997. Science 276:1857. Studies have demonstrated that endothelial cells, smooth muscle cells, and oxidized LDL cholesterol can activate CMV viral replication in infected mononuclear phagocytes which can lead to macrophage, endothelial cell, and vascular smooth muscle cell infection with CMV. CMV infected smooth muscle cells may then obtain growth advantages and contribute to proliferative responses in atherosclerosis due to CMV induced changes in expression of regulatory proteins. Speir et al. 1994. Science. 265:391.
A link between atherosclerosis and Helicobacter pylori has also been shown. H. pylori is a Gram-negative rod which has been implicated in the development of peptic ulcers, gastric carcinoma, and low-grade B cell lymphomas of the gastrointestinal tract. Schussheim et al. 1999, Drugs 57:283. An association of H. pylori infection with coronary disease has been suggested in which seropositivity conferred a two-fold increased risk of coronary artery disease among nearly 200 men. Mendall et al. 1994. Br. Heart J. 71:437; Danesh et al. 1997, Lancet 350:430; Cheng et al. 2000, Expert Opin. Investig. Drugs 9(11):2505; Muhlestein, J. B. 2000, Curr. Interv. Cardiol. Rep. 2(4):342. Another study supports this association when it was seen that elevated serum fibrinogen levels and total leucocyte count were found more often in those seropositive for H. pylori. Patel et al. 1995. B.M.J. 311:711.
A link between Chlamydia pneumoniae and vascular disease, such as atherosclerosis and coronary disease or coronary syndrome is also recognized. Schussheim et al., 1999, Drugs 57:283; Roivainen et al. 2000, Circulation 101(3):252; Muhlestein Curr. Interv. Cardiol. Rep. 2(4):342; Danesh et al. 1997, Lancet 350:430; Cheng et al. 2000, Expert Opin. Investig. Drugs 9(11):2505; Muhlestein, J. B. 2000, Curr. Interv. Cardiol. Rep. 2(4):342. Although Chlamydia is able to infect a number of cell types, the bacteria's ability to infect mononuclear phagocytes is thought to be pivotal to its role in the development or modulation of vascular disease, especially atherosclerosis. Mononuclear phagocytes are thought to spread infection from the respiratory tract to other organ systems based upon Chlamydia to remain metabolically active for at least 10 days in mononuclear phagocytes infected in vitro. Moazed et al. 1998. J. Infect Des. 177:1322. Chlamydia can also stimulate the secretion of proinflammatory cytokines such as tumor necrosis factor-.alpha., interleukin [IL]-1 and interferon-.gamma. from monocytes and T cells. Saikku, P. 1997. J. Infect. Dis. 104:53; Kol et al. 1998. Circulation 98:300; Halne, S. 1997. Scand. J. Immunol. 45:378.
Several seroepidemiological studies now associate Chlamydia infection with atherosclerosis and promote the organism as a major pathological factor of this general disease process. Saikku, P. 1997. Scand. J. Infect. Dis. 104:53; Campbell et al. 1998. Emerg. Infect. Dis. 4:571. Recently, C. pneumoniae-reactive T lymphocytes have been detected in human atherosclerotic plaques of the carotid artery. Mosorin, M., 2000, Arterioscler. Thromb. Vasc. Biol. 20:1061. The authors of this study suggest that Chlamydia, which is commonly detected in atherosclerotic plaque of the carotid and coronary arteries, causes T-cell activation and accumulation and this contributes to the maintenance of the inflammatory reaction in artherogenesis.
At least one epidemiological study has found that Chlamydia may be present as an associated agent in neurological infections. See, Koskiniemi, M. et al., 1996, Europ. Neurol., 36(3):60-63. A human.